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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 25 October 2011, Vol.108(43), pp.E934-42
    Description: Animals lacking complement factors C1q, C2, C3, or C4 have severely impaired Ab responses, suggesting a major role for the classic pathway. The classic pathway is primarily initiated by antigen-Ab complexes. Therefore, its role for primary Ab responses seems paradoxical because only low amounts of specific Abs are present in naive animals. A possible explanation could be that the classic pathway is initiated by IgM from naive mice, binding with sufficient avidity to the antigen. To test this hypothesis, a knock-in mouse strain, Cμ13, with a point mutation in the gene encoding the third constant domain of the μ-heavy chain was constructed. These mice produce IgM in which proline in position 436 is substituted with serine, a mutation previously shown to abrogate the ability of mouse IgM to activate complement. Unexpectedly, the Ab response to sheep erythrocytes and keyhole limpet hemocyanin in Cμ13 mice was similar to that in WT mice. Thus, although secreted IgM and the classic pathway activation are both required for the normal primary Ab response, this does not require that IgM activate C. This led us to test Ab responses in animals lacking one of three other endogenous activators of the classic pathway: specific intracellular adhesion molecule-grabbing nonintegrin R1, serum amyloid P component, and C-reactive protein. Ab responses were also normal in these animals.
    Keywords: Antibody Formation -- Immunology ; Complement Pathway, Classical -- Immunology ; Complement System Proteins -- Immunology ; Immunoglobulin Mu-Chains -- Immunology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 01 October 2013, Vol.110(40), pp.16115-20
    Description: Systemic amyloid A (AA) amyloidosis is a serious complication of chronic inflammation. Serum AA protein (SAA), an acute phase plasma protein, is deposited extracellularly as insoluble amyloid fibrils that damage tissue structure and function. Clinical AA amyloidosis is typically preceded by many years of active inflammation before presenting, most commonly with renal involvement. Using dose-dependent, doxycycline-inducible transgenic expression of SAA in mice, we show that AA amyloid deposition can occur independently of inflammation and that the time before amyloid deposition is determined by the circulating SAA concentration. High level SAA expression induced amyloidosis in all mice after a short, slightly variable delay. SAA was rapidly incorporated into amyloid, acutely reducing circulating SAA concentrations by up to 90%. Prolonged modest SAA overexpression occasionally produced amyloidosis after long delays and primed most mice for explosive amyloidosis when SAA production subsequently increased. Endogenous priming and bulk amyloid deposition are thus separable events, each sensitive to plasma SAA concentration. Amyloid deposits slowly regressed with restoration of normal SAA production after doxycycline withdrawal. Reinduction of SAA overproduction revealed that, following amyloid regression, all mice were primed, especially for rapid glomerular amyloid deposition leading to renal failure, closely resembling the rapid onset of renal failure in clinical AA amyloidosis following acute exacerbation of inflammation. Clinical AA amyloidosis rarely involves the heart, but amyloidotic SAA transgenic mice consistently had minor cardiac amyloid deposits, enabling us to extend to the heart the demonstrable efficacy of our unique antibody therapy for elimination of visceral amyloid.
    Keywords: 3rs ; Disease Model ; Amyloid -- Metabolism ; Amyloidosis -- Physiopathology ; Inflammation -- Complications ; Serum Amyloid A Protein -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    Language: English
    In: Nature, 04 November 2010, Vol.468(7320), pp.93-7
    Description: Accumulation of amyloid fibrils in the viscera and connective tissues causes systemic amyloidosis, which is responsible for about one in a thousand deaths in developed countries. Localized amyloid can also have serious consequences; for example, cerebral amyloid angiopathy is an important cause of haemorrhagic stroke. The clinical presentations of amyloidosis are extremely diverse and the diagnosis is rarely made before significant organ damage is present. There is therefore a major unmet need for therapy that safely promotes the clearance of established amyloid deposits. Over 20 different amyloid fibril proteins are responsible for different forms of clinically significant amyloidosis and treatments that substantially reduce the abundance of the respective amyloid fibril precursor proteins can arrest amyloid accumulation. Unfortunately, control of fibril-protein production is not possible in some forms of amyloidosis and in others it is often slow and hazardous. There is no therapy that directly targets amyloid deposits for enhanced clearance. However, all amyloid deposits contain the normal, non-fibrillar plasma glycoprotein, serum amyloid P component (SAP). Here we show that administration of anti-human-SAP antibodies to mice with amyloid deposits containing human SAP triggers a potent, complement-dependent, macrophage-derived giant cell reaction that swiftly removes massive visceral amyloid deposits without adverse effects. Anti-SAP-antibody treatment is clinically feasible because circulating human SAP can be depleted in patients by the bis-d-proline compound CPHPC, thereby enabling injected anti-SAP antibodies to reach residual SAP in the amyloid deposits. The unprecedented capacity of this novel combined therapy to eliminate amyloid deposits should be applicable to all forms of systemic and local amyloidosis.
    Keywords: Amyloid -- Drug Effects ; Amyloidosis -- Prevention & Control ; Antibodies -- Immunology ; Serum Amyloid P-Component -- Antagonists & Inhibitors
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 4
    Language: English
    In: Gastroenterology, April 2012, Vol.142(4), pp.897-906
    Description: Hepatocyte growth factor/scatter factor (HGF/SF) stimulates hepatocyte DNA synthesis and protects against apoptosis; in vivo it promotes liver regeneration and reduces fibrosis. However, its therapeutic value is limited by its complex domain structure, high cost of production, instability, and poor tissue penetration due to sequestration by heparin sulfate proteoglycans (HSPGs). Using protein engineering techniques, we created a full-length form of HGF/SF (called HP21) and a form of the small, naturally occurring HGF/SF fragment, NK1 (called 1K1), which have reduced affinity for HSPG. We characterized the stability and proliferative and anti-apoptotic effects of these variants in primary human hepatocytes and in rodents. Analytical ultracentrifugation showed that 1K1 and NK1 were more stable than the native, full-length protein. All 4 forms of HGF/SF induced similar levels of DNA synthesis in human hepatocytes; 1K1 and NK1 required heparin, an HSPG analogue, for full agonistic activity. All the proteins reduced levels of Fas ligand–mediated apoptosis, reducing the activity of caspase-3/7 and cleavage of poly(adenosine diphosphate–ribose) polymerase. 1K1 was more active than NK1 in rodents; in healthy mice, 1K1 significantly increased hepatocyte DNA synthesis, and in mice receiving carbon tetrachloride, it reduced fibrosis. In rats, after 70% partial hepatectomy, daily administration of 1K1 for 5 days significantly increased liver mass and the bromodeoxyuridine labeling index compared with mice given NK1. 1K1, an engineered form of the small, naturally occurring HGF/SF fragment NK1, has reduced affinity for HSPG and exerts proliferative and antiapoptotic effects in cultured hepatocytes. In rodents, 1K1 has antifibrotic effects and promotes liver regeneration. The protein has better stability and is easier to produce than HGF/SF and might be developed as a therapeutic for acute and chronic liver disease.
    Keywords: Growth Factor ; Cirrhosis ; Mouse Model ; Binding Mutant ; Medicine
    ISSN: 0016-5085
    E-ISSN: 1528-0012
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  • 5
  • 6
    Language: English
    In: Journal of Cardiovascular Magnetic Resonance, 01 February 2011, Vol.13(Suppl 1), p.O60
    Description: From: 2011 SCMR/Euro CMR Joint Scientific Sessions Nice, France 3-6 February 2011 Author details1-Centre for Advanced Biomedical Imaging, University College London, London, UKEMPTY2-Robert Steiner MRI Unit, Imperial College London, London, UKEMPTY3-Centre for Amyloidosis and Acute Phase Proteins, Division...
    Keywords: Medicine
    ISSN: 1097-6647
    E-ISSN: 1532-429X
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  • 7
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 10 August 2004, Vol.101(32), pp.11749-54
    Description: A humanized mouse bearing the HLA-DR2 (DRA/DRB1*1501) protein associated with multiple sclerosis (MS) and the myelin basic protein (MBP) 85-99-specific HLA-DR2-restricted T cell receptor from an MS patient has been used to examine the effectiveness of modified amino acid copolymers poly(F,Y,A,K)n and poly-(V,W,A,K)n in therapy of MBP 85-99-induced experimental autoimmune encephalomyelitis (EAE) in comparison to Copolymer 1 [Copaxone, poly(Y,E,A,K)n]. The copolymers were designed to optimize binding to HLA-DR2. Vaccination, prevention, and treatment of MBP-induced EAE in the humanized mice with copolymers FYAK and VWAK ameliorated EAE more effectively than Copolymer 1, reduced the number of pathological lesions, and prevented the up-regulation of human HLA-DR on CNS microglia. Moreover, VWAK inhibited MBP 85-99-specific T cell proliferation more efficiently than either FYAK or Copolymer 1 and induced anergy of HLA-DR2-restricted transgenic T cells as its principle mechanism. In contrast, FYAK induced proliferation and a pronounced production of the antiinflammatory T helper 2 cytokines IL-4 and IL-10 from nontransgenic T cells as its principle mechanism of immunosuppression. Thus, copolymers generated by using different amino acids inhibited disease using different mechanisms to regulate T cell responses.
    Keywords: Encephalomyelitis, Autoimmune, Experimental -- Drug Therapy ; Peptide Fragments -- Therapeutic Use ; Peptides -- Therapeutic Use
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 8
    Language: English
    In: Molecular Therapy, March 2013, Vol.21(3), pp.602-609
    Description: Familial hypercholesterolemia (FH) is a genetic disorder characterized by extremely high levels of plasma low-density lipoprotein (LDL), due to defective LDL receptor-apolipoprotein B (APOB) binding. Current therapies such as statins or LDL apheresis for homozygous FH are insufficiently efficacious at lowering LDL cholesterol or are expensive. Treatments that target APOB100, the structural protein of LDL particles, are potential therapies for FH. We have developed a series of APOB-directed splice-switching oligonucleotides (SSOs) that cause the expression of APOB87, a truncated isoform of APOB100. APOB87, like similarly truncated isoforms expressed in patients with a different condition, familial hypobetalipoproteinemia, lowers LDL cholesterol by inhibiting very low–density lipoprotein (VLDL) assembly and increasing LDL clearance. We demonstrate that these “APO-skip ” SSOs induce high levels of exon skipping and expression of the APOB87 isoform, but do not substantially inhibit APOB48 expression in cell lines. A single injection of an optimized APO-skip SSO into mice transgenic for human resulted in abundant exon skipping that persists for 〉6 days. Weekly treatments generated a sustained reduction in LDL cholesterol levels of 34–51% in these mice, superior to pravastatin in a head-to-head comparison. These results validate APO-skip SSOs as a candidate therapy for FH.
    Keywords: Medicine ; Biology
    ISSN: 1525-0016
    E-ISSN: 1525-0024
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  • 9
    In: Immunology, July 2014, Vol.142(3), pp.414-420
    Description: No deficiency of human C‐reactive protein (), or even structural polymorphism of the protein, has yet been reported so its physiological role is not known. Here we show for the first time that ‐deficient mice are remarkably susceptible to infection and are protected by reconstitution with isolated pure human , or by anti‐pneumococcal antibodies. Autologous mouse is evidently essential for innate resistance to pneumococcal infection before antibodies are produced. Our findings are consistent with the significant association between clinical pneumococcal infection and non‐coding human gene polymorphisms which affect expression. Deficiency or loss of function variation in may therefore be lethal at the first early‐life encounter with this ubiquitous virulent pathogen, explaining the invariant presence and structure of in human adults.
    Keywords: Anti‐Nuclear Antibodies ; C‐Reactive Protein ; Host Resistance ; Mouse Knockout ; Pneumococcal Infection
    ISSN: 0019-2805
    E-ISSN: 1365-2567
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  • 10
    Language: English
    In: Amyloid, 01 June 2013, Vol.20(2), pp.93-98
    Description: We report the in vivo evaluation, in a murine model, of MRI measurements of the extracellular volume fraction (ECV) for the detection and monitoring of systemic amyloidosis. A new inducible transgenic model was used, with increased production of mouse serum amyloid A protein controlled by oral...
    Keywords: Ecv ; Gadolinium ; Medical Imaging ; Murine Model ; Magnetic Resonance ; Serum Amyloid A Protein ; Anatomy & Physiology
    ISSN: 1350-6129
    E-ISSN: 1744-2818
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